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Superfamily 4 Flashcards

1
Q

What receptors are included in SF 4?

A

Intracellular/ nuclear receptors

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2
Q

How large is superfamily 4?

A

It is a small superfamily
It has less that 50 types of receptors
Compared to SF 2 with 900,000

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3
Q

How is SF 4 divided?

A

Class l
Class ll
Hybrid class

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4
Q

What type of receptor is in class l?

A

Receptors for steroid hormones
E.G oestrogen receptor family
Glucocorticoid hormone receptor (cortisol)
Mineralocorticoid hormone receptor (aldosterone)
Androgen receptors
Progesterone receptors

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5
Q

What receptors are part of class ll?

A

Receptors for lipid mediators already in the cell
LXR
PPARs
FXR
SXR
Orphan nuclear receptors

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6
Q

What is the LXR receptor?

A

Liver oxysterol receptor
Cholesterol sensor

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7
Q

What is the PPAR receptor?

A

Peroxidase proliferator activated receptors for fatty acids

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8
Q

What is the FXR receptor?

A

The farnesoid receptor for bile acids

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9
Q

What is the SXR receptor?

A

Steroid and xenobiotic receptor
Regulates the clearance of drugs

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10
Q

Give an example of an orphan nuclear receptor in class ll

A

RXR retinoid receptor for derivatives of retinoic acid

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11
Q

What type of receptors belong to the hybrid class of SF 4?

A

Miscellaneous receptors that are mainly for endocrine mediators

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12
Q

What receptors are found in the hybrid class?

A

Thyroid hormone receptor
Vitamin D receptor
Retinoic acid (vit A) receptor
All lipophilic

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13
Q

What is the significant difference in SF 4s structure?

A

There are no transmembrane alpha helixes
Because it is found completely intracellularly
It’s a single protein chain

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14
Q

Where will the ligand bind to in SF 4 receptor?

A

Close to the C terminal
The activation function 2 site
Other ligands May bind here too to anchor them within the cell (especially in the receptors inactive state)

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15
Q

Explain what the regulatory domain is

A

found at the N terminal, activation function 1 site (ligands may use this as a scaffold) changes to this region may alter the activity of the receptor

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16
Q

Explain what the zinc fingers are and where they’re found

A

Found at the DNA binding domain
There are two zinc fingers
Zinc atom surrounded by 15 amino acids
Folded when the receptor is inactive
When the receptor changes shape due to activation the fingers will open up and act as little hooks for nucleic acids to hook onto

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17
Q

Where are class l nuclear receptors found?

A

Mainly present in the cytoplasm, sometimes located at the nuclear membrane and perinuclear region .
Will be complexed with heat shock protein 90 in the absence of a ligand to keep it anchored in the right place

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18
Q

Which ligands do Class l receptors recognise?

A

They mainly recognise and have high affinity for endocrine ligands

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19
Q

How will class l receptors operate?

A

They operate as homodimers on activation
Allosteric interactions may be important for receptor activity or cooperativity

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20
Q

How can class l receptors act as transcription factors?

A

When it activated by ligand binding the zinc fingers open and can attach to nucleic acids to a hormone responsive element upstream of the promoter region
This allows it to regulate gene transcription

21
Q

How does the ligand activated receptor regulate transcription?

A

Can activate genes or repress constitutively expressed genes on binding to HRE
Often involved in negative feedback gene expression
Can increase or decrease expression of its own or of others steroid hormone receptors

22
Q

How does the steroid hormone travel?

A

Steroid hormone is quite lipophilic
It travels in the blood by binding to steroid hormone binding globulins which deliver it to the ligand cell membrane where it can easily diffuse into the cell

23
Q

What happens once steroid hormone diffuses into the cell?

A

The Steroid hormone will bind to an unoccupied receptor causing it to irreversibly dissociate from the heat shock 90 protein
The allosteric change in shape due to activation will unmask the zinc fingers

24
Q

What are the properties of class ll nuclear receptors?

A

They’re already present in the nucleus (often bind to DNA in the absence of a ligand)
Frequently operate as heterodimers
Mainly recognise lipid ligands already present in the cell
Low affinity ligand binding site

25
What do class ll nuclear receptors do?
Tend to mediate positive feedback and amplification Ligand promotes dissociation of receptor from DNA to remove inhibition of gene expression influencing the positive feedback Will often influence expression of enzymes influencing metabolism of lipids and of prescription drugs
26
How does methylation work to co-regulate gene expression
DNA methylation silences gene expression Demethylating enzymes can enhance expression
27
How does acetylation work as Co-regulators of gene expression?
Deacetylation of histones suppresses gene expression by winding DNA more tightly together Acetylating enzymes will enhance expression
28
What conditions are mutations of methylating and acteylating enzymes associated with?
Inflammatory disease Malignancies
29
List some of the therapeutic potentials of oestrogens
Control of reproductive function Bone metabolism Cardiovascular disease Alzheimer’s disease Hot flushes, mood changes
30
What are the splice variants of the oestrogen receptor?
ER alpha ER beta
31
What are the difference between ER alpha and ER beta?
They differ in regard to tissue distribution There is less than 30% overlap in the genes which they regulate Thought to be selective for different co activators and co repressors ER beta is found in the mitochondrial genome and can influence mitochondrial genes
32
What agents are being identified for nuclear receptor therapeutics?
Selective nuclear receptor modulators (SNuRMs) Selective nuclear receptor degraders (SNuRDs)
33
What do SNuRMs do?
Activate subset of functions of natural ligand So natural ligands can let all coregulators and cosupressors bind Similar to agonist trafficking The modulator will only activate a subset of functions that the natural ligand would activate
34
Give two examples of SNuRMs
Raloxifene Tamoxifen
35
How does raloxifene work?
Acts as an agonist at oestrogen receptors in some tissues such as bone to prevent post menopausal osteoporosis Acts as an oestrogen receptor antagonist in other tissues such as the uterus and breasts to reduce the incidence and progression of cancer
36
What other possible uses are there for SNuRMs?
SNuRMs could be useful for other steroid hormone receptors for example to separate androgenic and anabolic effects of androgenic receptors
37
Explain the example of tamoxifen as a SNuRM
Tamoxifen acts as an oestrogen receptor antagonist to help slow the progression of breast cancer However resistance emerges after two years on the treatment At this point it will change from being an oestrogen antagonist to an oestrogen agonist which is counter productive in the fight against breast cancer
38
What are theories to explain the change of tamoxifens activity?
Preferential survival/ proliferation of mutant receptors with different coregulator profiles Temporal alterations in expression or activity of coregulators Altered acetylation of histones or methylation of DNA would influence which coregulators bind Phosphorylation of the receptor or of coregulators by GPCR activated or tyrosine kinase receptors dependent protein kinases
39
What do SNuRDs do?
They regulate cell nuclear receptor turnover
40
How are SNuRDs used?
As therapeutic strategies to down regulate receptor numbers in conditions associated with nuclear receptor over expression
41
Give an example of a SNuRD
Fluvestrant Used for eostrogen receptor positive metastatic breast cancer
42
Why is there thought to be a cell surface oestrogen receptor as well as the intracellular nuclear receptors?
Some say that the response seen from oestrogen receptor activation are too quick to be reliant on gene expression
43
What are the theories behind an extracellular oestrogen receptor?
Translocation of the intracellular oestrogen receptor to the cell surface membrane Due to genome sequencing it is now known that there is G protein coupled receptor known as GPR-30 for oestrogen associated with activation of adenylate cyclase and phospholipase C-beta
44
What is the significance of the GPR-30 receptor?
It is implicated in some oestrogen signalling pathways including cardioprotection, neuro protection and bone preservation The signal transduction is independent of direct interaction of the receptor with genome - does not require protein synthesis
45
Give some examples of recent nuclear receptor therapeutics
Spirolactone Rosiglitazone Fibrates SXR modulators
46
What is spirolactone?
An aldosterone receptor antagonist Reduces sodium leading to fluid loss in order to aid in heart failure
47
What is rosiglitazone?
A PPAR gamma agonist as a novel anti diabetic agent It has insulin sensitising action
48
How do fibrates work?
They are PPAR alpha agonists to treat dyslipidaemia They reduce serum triglyceride levels
49
How do SXR modulators work? Steroid and xenobiotic receptor modulator
Would decrease enzyme activity to prolong the drugs time of action, it would not be cleared as quickly This could improve a particular drugs efficacy Could change the distribution of the drug by skipping the first pass metabolism and increase the drugs bioavailability

Pharmacology (18 decks)

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